ALC-2 expression has proven to be a useful marker of
cardiac muscle chamber distinction, development and differentiation. ALC-2 shows a pattern distinct from atrial essential light chain
(ALC-1) during cardiogenesis. ALC-2 expression in adult murine hearts is
cardiac-specific throughout
embryonic days 8-16, and from day 12 and on is restricted to
atria, showing very low levels in
aorta and undetectable in
ventricles,
skeletal muscle,
uterus, and
liver. This
atrial patterning occurs prior to
septation. Expression of ALC-2 has been shown to correlate with expression of
alpha-myosin heavy chain in
cardiac atria of non-human primates. ALC-2 and VLC-2 appear to function in the stabilization of
thick filaments and regulation of
contractility in the vertebrate heart. Functional insights into ALC-2 function have come from studies employing transgenesis. A study in which the
ventricular isoform of regulatory light chain was overexpressed to replace the ALC-2 in cardiac
atria was performed. This substitution resulted in
atrial myocytes that
contract and
relax more forcefully and quickly, resulting in
atrial cardiomyocytes that behave as
ventricular cardiomyocytes. In disease models, ALC-2 expression in some instances can be downregulated and replaced by the
ventricular isoform (VLC-2). In spontaneously
hypertensive rats, VLC-2
mRNA expression is three times higher in
atria; and this change precedes any detectable pressure overloading of the heart, suggesting that this change is a very early functional adaptation to
cardiac hypertrophy. Moreover, in a porcine model of
atrial fibrillation, VLC-2
mRNA expression showed the greatest change, being upregulated 9.4-fold and 7.3-fold in left and right
atria, respectively. In a porcine model of left
atrial remodeling following
mitral regurgitation, VLC-2 was shown to be upregulated. Human ALC-2 is phosphorylated at its
N-terminus at
Serine-15 by a cardiac-specific
myosin light chain kinase; ALC-2 has a
serine at position 14, which is an
Asparagine in the
ventricular isoform that is shown to be deamidated (thus producing a negative charge similar to
phosphorylation). Whether
serine-14 of human ALC-2 is also phosphorylated remains to be determined. Endogenous
phosphorylation level is around 30% of the total ALC-2.
Alpha(1)-adrenergic stimulation by
phenylephrine in
atrial muscle strips showed an 80% increase in ALC-2
phosphorylation coordinate with enhanced
contractile force, which was inhibited by both
Rho kinase and
myosin light chain kinase inhibition. In a canine model of
atrial fibrillation, decreased
atrial contractility was associated with decreased ALC-2 and
myosin binding protein C phosphorylation. Moreover, the slow force response induced by stretch in human
atrial muscle was shown to be modulated by enhanced
phosphorylation of ALC-2 by
myosin light chain kinase. ==Clinical Significance==